title: Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2.
abstract: AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Theophilus I
authors.initials: TI
authors.lastname: Emeto
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Moxon
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Erik
authors.initials: E
authors.lastname: Biros
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rush
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Paula
authors.initials: P
authors.lastname: Clancy
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Lynn
authors.initials: L
authors.lastname: Woodward
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Moran
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Roby J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: *The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
authors.forename: Tam
authors.initials: T
authors.lastname: Nguyen
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Walker
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D017544:Aortic Aneurysm, Abdominal / Q000503:physiopathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D054832:Urocortins / Q000097:blood / Q000502:physiology*
chemical_list: C101531:CRF receptor type 2; D016209:Interleukin-8; D018019:Receptors, Corticotropin-Releasing Hormone; C426705:UCN2 protein, human; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone; D051057:Proto-Oncogene Proteins c-akt